KF24345, an adenosine uptake inhibitor, ameliorates the severity and mortality of lethal acute pancreatitis via endogenous adenosine in mice

• Published in: European journal of pharmacology Vol. 454; no. 1; pp. 85 - 93
• Main Authors: Noji, Tohru, Nan-ya, Ken-ichiro, Mizutani, Mirai, Katagiri, Chikako, Sano, Jun-ichi, Takada, Chie, Nishikawa, Satoshi, Karasawa, Akira, Kusaka, Hideaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2002
• Subjects: Acute Disease; Acute pancreatitis; Adenosine; Adenosine - antagonists & inhibitors; Adenosine - blood; Amylases - blood; Animals; Choline Deficiency - complications; Diet; Female; KF24345; L-Lactate Dehydrogenase - blood; Mice; Mortality; Neurotransmitter Uptake Inhibitors - pharmacology; Organ Size; Pancreas - drug effects; Pancreatitis - drug therapy; Pancreatitis - etiology; Pancreatitis - mortality; Pyrimidinones - pharmacology; Quinazolines - pharmacology; Time Factors; TNF-α (Tumor necrosis factor-α); Tumor Necrosis Factor-alpha - metabolism; Uptake inhibition; KF24345; Uptake inhibition; TNF-α (Tumor necrosis factor-α); Adenosine; Acute pancreatitis; Mortality
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)02476-7

Adenosine protects against cellular damage and dysfunction under several adverse conditions including inflammation and ischemia. In this study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1
H,3
H)-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on experimental acute pancreatitis induced by choline-deficient and ethionine-supplemented diet in mice. KF24345, administered with the diet onset and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and serum tumor necrosis factor-α elevation and ultimately decreased mortality. Therapeutic treatment with KF24345, which started 32 h after the diet onset, also decreased mortality. The beneficial effect of KF24345 on mortality was abolished by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-
a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A
2A receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet onset increased plasma adenosine concentrations in mice with acute pancreatitis. These results suggest that KF24345 shows anti-pancreatitis effects via endogenous adenosine and adenosine A
2A receptors. The adenosine uptake inhibition could be a new therapeutic approach for acute pancreatitis.